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Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibilit...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9872243/ https://www.ncbi.nlm.nih.gov/pubmed/35788059 http://dx.doi.org/10.1136/gutjnl-2022-327196 |
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author | Buch, Stephan Innes, Hamish Lutz, Philipp Ludwig Nischalke, Hans Dieter Marquardt, Jens U Fischer, Janett Weiss, Karl Heinz Rosendahl, Jonas Marot, Astrid Krawczyk, Marcin Casper, Markus Lammert, Frank Eyer, Florian Vogel, Arndt Marhenke, Silke von Felden, Johann Sharma, Rohini Atkinson, Stephen Rahul McQuillin, Andrew Nattermann, Jacob Schafmayer, Clemens Franke, Andre Strassburg, Christian Rietschel, Marcella Altmann, Heidi Sulk, Stefan Thangapandi, Veera Raghavan Brosch, Mario Lackner, Carolin Stauber, Rudolf E Canbay, Ali Link, Alexander Reiberger, Thomas Mandorfer, Mattias Semmler, Georg Scheiner, Bernhard Datz, Christian Romeo, Stefano Ginanni Corradini, Stefano Irving, William Lucien Morling, Joanne R Guha, Indra Neil Barnes, Eleanor Ansari, M Azim Quistrebert, Jocelyn Valenti, Luca Müller, Sascha A Morgan, Marsha Yvonne Dufour, Jean-François Trebicka, Jonel Berg, Thomas Deltenre, Pierre Mueller, Sebastian Hampe, Jochen Stickel, Felix |
author_facet | Buch, Stephan Innes, Hamish Lutz, Philipp Ludwig Nischalke, Hans Dieter Marquardt, Jens U Fischer, Janett Weiss, Karl Heinz Rosendahl, Jonas Marot, Astrid Krawczyk, Marcin Casper, Markus Lammert, Frank Eyer, Florian Vogel, Arndt Marhenke, Silke von Felden, Johann Sharma, Rohini Atkinson, Stephen Rahul McQuillin, Andrew Nattermann, Jacob Schafmayer, Clemens Franke, Andre Strassburg, Christian Rietschel, Marcella Altmann, Heidi Sulk, Stefan Thangapandi, Veera Raghavan Brosch, Mario Lackner, Carolin Stauber, Rudolf E Canbay, Ali Link, Alexander Reiberger, Thomas Mandorfer, Mattias Semmler, Georg Scheiner, Bernhard Datz, Christian Romeo, Stefano Ginanni Corradini, Stefano Irving, William Lucien Morling, Joanne R Guha, Indra Neil Barnes, Eleanor Ansari, M Azim Quistrebert, Jocelyn Valenti, Luca Müller, Sascha A Morgan, Marsha Yvonne Dufour, Jean-François Trebicka, Jonel Berg, Thomas Deltenre, Pierre Mueller, Sebastian Hampe, Jochen Stickel, Felix |
author_sort | Buch, Stephan |
collection | PubMed |
description | OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10(−9), OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10(−5), OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10(−44)). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis. |
format | Online Article Text |
id | pubmed-9872243 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-98722432023-01-25 Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study Buch, Stephan Innes, Hamish Lutz, Philipp Ludwig Nischalke, Hans Dieter Marquardt, Jens U Fischer, Janett Weiss, Karl Heinz Rosendahl, Jonas Marot, Astrid Krawczyk, Marcin Casper, Markus Lammert, Frank Eyer, Florian Vogel, Arndt Marhenke, Silke von Felden, Johann Sharma, Rohini Atkinson, Stephen Rahul McQuillin, Andrew Nattermann, Jacob Schafmayer, Clemens Franke, Andre Strassburg, Christian Rietschel, Marcella Altmann, Heidi Sulk, Stefan Thangapandi, Veera Raghavan Brosch, Mario Lackner, Carolin Stauber, Rudolf E Canbay, Ali Link, Alexander Reiberger, Thomas Mandorfer, Mattias Semmler, Georg Scheiner, Bernhard Datz, Christian Romeo, Stefano Ginanni Corradini, Stefano Irving, William Lucien Morling, Joanne R Guha, Indra Neil Barnes, Eleanor Ansari, M Azim Quistrebert, Jocelyn Valenti, Luca Müller, Sascha A Morgan, Marsha Yvonne Dufour, Jean-François Trebicka, Jonel Berg, Thomas Deltenre, Pierre Mueller, Sebastian Hampe, Jochen Stickel, Felix Gut Hepatology OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10(−9), OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10(−5), OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10(−44)). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis. BMJ Publishing Group 2023-02 2022-07-04 /pmc/articles/PMC9872243/ /pubmed/35788059 http://dx.doi.org/10.1136/gutjnl-2022-327196 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Hepatology Buch, Stephan Innes, Hamish Lutz, Philipp Ludwig Nischalke, Hans Dieter Marquardt, Jens U Fischer, Janett Weiss, Karl Heinz Rosendahl, Jonas Marot, Astrid Krawczyk, Marcin Casper, Markus Lammert, Frank Eyer, Florian Vogel, Arndt Marhenke, Silke von Felden, Johann Sharma, Rohini Atkinson, Stephen Rahul McQuillin, Andrew Nattermann, Jacob Schafmayer, Clemens Franke, Andre Strassburg, Christian Rietschel, Marcella Altmann, Heidi Sulk, Stefan Thangapandi, Veera Raghavan Brosch, Mario Lackner, Carolin Stauber, Rudolf E Canbay, Ali Link, Alexander Reiberger, Thomas Mandorfer, Mattias Semmler, Georg Scheiner, Bernhard Datz, Christian Romeo, Stefano Ginanni Corradini, Stefano Irving, William Lucien Morling, Joanne R Guha, Indra Neil Barnes, Eleanor Ansari, M Azim Quistrebert, Jocelyn Valenti, Luca Müller, Sascha A Morgan, Marsha Yvonne Dufour, Jean-François Trebicka, Jonel Berg, Thomas Deltenre, Pierre Mueller, Sebastian Hampe, Jochen Stickel, Felix Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study |
title | Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study |
title_full | Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study |
title_fullStr | Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study |
title_full_unstemmed | Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study |
title_short | Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study |
title_sort | genetic variation in tert modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study |
topic | Hepatology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9872243/ https://www.ncbi.nlm.nih.gov/pubmed/35788059 http://dx.doi.org/10.1136/gutjnl-2022-327196 |
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